Recent Progress in Synthesis of Alkyl Fluorinated Compounds with Multiple Contiguous Stereogenic Centers

Organic fluorides are widely used in pharmaceuticals, agrochemicals, material sciences, and other fields due to the special physical and chemical properties of fluorine atoms. The synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers is the most challenging research area in synthetic chemistry and has received extensive attention from chemists. This review summarized the important research progress in the field over the past decade, including asymmetric electrophilic fluorination and the asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions), with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms.


Asymmetric Electrophilic Fluorination
The development of readily available and efficient sources of electrophilic fluorinating reagents, such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) (9, Figure 4) [30] and N-fluorobenzenesulfonimide (NFSI) (10, Figure 4) [31], has had a significant impact on catalytic asymmetric electrophilic fluorination, and encouraging progress has been made.In contrast, the synthesis of chiral alkyl fluorides with multiple contiguous stereogenic centers using nucleophilic fluorinating reagents is more difficult due to the poor reactivity of the fluorine anion.Asymmetric electrophilic fluorination catalyzed by transition metal catalysts or chiral organocatalysts is one of the typical methods used for the synthesis of

Asymmetric Electrophilic Fluorination
The development of readily available and efficient sources of electrophilic fluorinating reagents, such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) (9, Figure 4) [30] and N-fluorobenzenesulfonimide (NFSI) (10, Figure 4) [31], has had a significant impact on catalytic asymmetric electrophilic fluorination, and encouraging progress has been made.In contrast, the synthesis of chiral alkyl fluorides with multiple contiguous stereogenic centers using nucleophilic fluorinating reagents is more difficult due to the poor reactivity of the fluorine anion.Catalytic asymmetric dearomatization (CADA) [32][33][34][35][36][37][38][39] reactions via fluorin represent a powerful strategy for constructing chiral fluorine-containing compounds readily available aromatic derivatives.In 2011, Gouverneur et al. reported the organocatalyzed asymmetric dearomatization of indole derivatives 13 via ca fluorocyclization utilizing a cinchona alkaloid C1 as a catalyst and NFSI or Selectflu an electrophilic reagent (Scheme 1) [40].Enantioenriched fluorinated heterocycles 14 obtained with moderate to high enantioselectivities.Almost at the same time, Toste developed asymmetric electrophilic fluorination using a chiral anion phase-tra catalyst C2.Interestingly, benzothiophenes substrates 15 were converted to de fluorocyclization products 16 in high optical purity and good yield through C reactions via fluorination (Scheme 2) [25].The proposed catalytic mechanism is sho Scheme 2. Phosphate (2 equiv.)undergoes salt substitution with Selectfluor to pro the chiral ion pair, which is soluble in nonpolar solvents, and then the chiral ion pa mediate the fluorocyclization of the substrate 17.In 2017, You et al. developed asymm fluorinative dearomatization of tryptamine derivatives 19 under anion phase-tra catalysis, which entailed the use of Selectfluor as an electrophilic fluoride source chiral phosphate anion derived from BINOL backbone C3 as a catalyst (Scheme 3 They noticed that a proton sponge (PS) can effectively improve the reaction yie variety of fluorinated pyrroloindolines 20 bearing two contiguous quaternary stereo centers were obtained with excellent enantioselectivities (up to 97% ee) and high y (up to 92% yield).Regarding the exploration of the substrates' scope, tryptamines electron-withdrawing protecting groups (Boc, CO2Me, Cbz, and Fmoc) were tolerated.N-Boc protected tryptamines with different electron-withdrawing (5-CO2 CF3, 5-Cl, 5-Br, and 5-F) and electron-donating (5-MeO, 5-CH3, and 5t Bu) substitue the C5 position, which proceeded with excellent enantioselectivity.4,6-dihalo-substi substrates and 2-or 6-substituent of the indole moiety were also well tolerated to pr target products with high enantioselectivity.Substrates bearing higher steric hind substituents or simple H and methyl at the C7 position resulted in mod enantioselectivity.Control experiments suggested that the reaction proceeded bifunctional activation using a chiral BINOL-derived phosphate anion C3.Recentl asymmetric dearomatizing fluoroamidation of indole acetamide derivatives 21 us dicarboxylate phase-transfer catalyst C4 under mild conditions was develope Hamashima et al. (Scheme 4) [42].Indoles with various substitution patterns were su substrates, providing easy access to chiral fluoropyrroloindoline derivatives 22 in 50 yields and 74-97% ee.It is worth mentioning that the addition of an appropriate am of water to the reaction system was essential to facilitate the reaction and e reproducibility.[41].They noticed that a proton sponge (PS) can effectively improve the reaction yield.A variety of fluorinated pyrroloindolines 20 bearing two contiguous quaternary stereogenic centers were obtained with excellent enantioselectivities (up to 97% ee) and high yields (up to 92% yield).Regarding the exploration of the substrates' scope, tryptamines with electron-withdrawing protecting groups (Boc, CO 2 Me, Cbz, and Fmoc) were well tolerated.N-Boc protected tryptamines with different electron-withdrawing (5-CO 2 Et, 5-CF 3 , 5-Cl, 5-Br, and 5-F) and electron-donating (5-MeO, 5-CH 3 , and 5-t Bu) substituents at the C5 position, which proceeded with excellent enantioselectivity.4,6-dihalo-substituted substrates and 2-or 6-substituent of the indole moiety were also well tolerated to provide target products with high enantioselectivity.Substrates bearing higher steric hindrance substituents or simple H and methyl at the C7 position resulted in moderate enantioselectivity.Control experiments suggested that the reaction proceeded via bifunctional activation using a chiral BINOL-derived phosphate anion C3.Recently, the asymmetric dearomatizing fluoroamidation of indole acetamide derivatives 21 using a dicarboxylate phase-transfer catalyst C4 under mild conditions was developed by Hamashima et al. (Scheme 4) [42].Indoles with various substitution patterns were suitable substrates, providing easy access to chiral fluoropyrroloindoline derivatives 22 in 50-90% yields and 74-97% ee.It is worth mentioning that the addition of an appropriate amount of water to the reaction system was essential to facilitate the reaction and ensure reproducibility.Scheme 2. Phase transfer-catalyzed asymmetric dearomatized fluorocyclizations of benzothiophene derivatives [25].
In 2015, Wang et al. reported a one-pot reaction sequence of the organocatalytic asymmetric Friedel-Crafts addition of 4-nonsubstituted pyrazolones 24 to isatin-derived N-Boc ketimine 23 followed by diastereoselective electrophilic fluorination (Scheme 5) [43].By using 0.5 mol% quinine squaramide C5 as a catalyst, CH 2 Cl 2 as a solvent in the first step, NFSI as an electrophilic reagent, and K 2 CO 3 as a base in the second step, a variety of fluorinated oxindole-pyrazolone adducts 25 bearing vicinal tetrasubstituted stereocenters containing a C-F quaternary carbon were obtained with 88-96% yields, 95-99% ee, and >20:1 dr.In 2020, Šebesta and co-workers reported the squaramide C6-catalyzed asymmetric Mannich reaction of oxindole imines 23 with pyrazolones 24, followed by electrophilic diastereoselective fluorination (Scheme 6) [44].The reaction proceeded under liquid-assisted grinding conditions to provide oxindolyl fluoropyrazolone derivatives 25 with enantiomer purities up to a 99:1 enantiomeric ratio.The organocatalytic Domino Mannich reaction was also suitable for isoxazole, but the yield was slightly lower, with up to 52% ee.However, thiazolones and oxazolones were ineffective substrates.Notably, the ball-milling reaction was more efficient than that of the solution reaction.The ball milling reaction time could be greatly shortened to a few minutes, and the amount of solvent required for the reaction could be minimized.x FOR PEER REVIEW 7 of 48 In 2015, Wang et al. reported a one-pot reaction sequence of the organocatalytic asymmetric Friedel-Crafts addition of 4-nonsubstituted pyrazolones 24 to isatin-derived N-Boc ketimine 23 followed by diastereoselective electrophilic fluorination (Scheme 5) [43].By using 0.5 mol% quinine squaramide C5 as a catalyst, CH2Cl2 as a solvent in the Scheme 4. Phase transfer-catalyzed asymmetric dearomatized fluoroamidation of indole derivatives [42].

Molecules 2024, 29, x FOR PEER REVIEW
ineffective substrates.Notably, the ball-milling reaction was more efficient than that of the solution reaction.The ball milling reaction time could be greatly shortened to a few minutes, and the amount of solvent required for the reaction could be minimized.Step 1 ineffective substrates.Notably, the ball-milling reaction was more efficient than that of the solution reaction.The ball milling reaction time could be greatly shortened to a few minutes, and the amount of solvent required for the reaction could be minimized.Step 1 In 2018, Lu et al. reported an enantioselective sequential Nazarov cyclization/electrophilic fluorination of divinyl ketone derivatives 26 catalyzed by the thiazoline iminopyridine (TIP)-Co complex C7, yielding various substituted chiral α-fluorinated cyclopentenones 27 with 48-96% yields, 44-97% ee, and >20:1 dr (Scheme 7) [45].Further derivatization of the α-fluorinated cyclopentenones allowed the construction of chiral cyclopentenols with three contiguous stereocenters and the synthesis of chiral α-single fluorine substituted cyclopentenones.Additionally, the gram-scale experiment proceeded well with little loss of ee values for the target compounds.

Asymmetric Elaboration of Fluorine-Containing Substrates
Asymmetric allylic alkylation reactions, Mannich addition r addition reactions, aldol reactions, and cross-coupling reactions of fl substrates represent another classical approach for constructing m stereocenters containing C-F stereocenters.

Allylic Alkylation Reactions
Transition metal-catalyzed asymmetric allylic substitution reactio of the most powerful methods for building up stereocenters.Asymmetr reactions of prochiral fluorine-containing nucleophiles provide an effi strategy for the synthesis of chiral alkyl fluorinated molecules bearing t stereogenic centers.
α-Pyridine-α-fluoro esters are important synthons for the sy molecules containing both a fluorine atom and a pyridine ring.Howe fluoro esters are less nucleophilic, and the potential inactivation or poi through the coordination of heteroaromatics will result in poor contro stereoselectivities.In 2019, Hartwig, He and co-workers reported th allylic alkylation of α-fluorinated azaaryl acetates 33 with cinnamyl me utilizing the combination of a chiral cyclometalated iridium catalyst C9 ligated to (R,R)-BPE (L1) (Scheme 10) [60].In the presence of 1,8-diazabi 7-ene (DBU) as a base, the allylic substitution reaction gave fluorinate vicinal quaternary and tertiary stereogenic centers in yields generally > 97-99% ee.A variety of alkyl-and aryl-substituted allylic esters, α-fl acetates, ketones, and amides were amenable to this Cu/Ir catalytic desired products with satisfactory results.Notably, the copper cat catalyst could, respectively, control the configuration of the nucleop unstabilized enolate and the electrophilic carbon of allylic carbonat system.Scheme 9. Enantio-and diastereoselective synthesis of acyclic compound possessing tertiary alkyl fluoride and ester [47].

Asymmetric Elaboration of Fluorine-Containing Substrates
Asymmetric allylic alkylation reactions, Mannich addition reactions, Michael addition reactions, aldol reactions, and cross-coupling reactions of fluorine-containing substrates represent another classical approach for constructing multiple contiguous stereocenters containing C-F stereocenters.
α-Pyridine-α-fluoro esters are important synthons for the synthesis of chiral molecules containing both a fluorine atom and a pyridine ring.However, α-pyridine-α-fluoro esters are less nucleophilic, and the potential inactivation or poisoning of catalysts through the coordination of heteroaromatics will result in poor control of reactivity and stereoselectivities.In 2019, Hartwig, He and co-workers reported the stereodivergent allylic alkylation of α-fluorinated azaaryl acetates 33 with cinnamyl methyl carbonates 34 utilizing the combination of a chiral cyclometalated iridium catalyst C9 and a Cu complex ligated to (R,R)-BPE (L1) (Scheme 10) [60].In the presence of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) as a base, the allylic substitution reaction gave fluorinated products within vicinal quaternary and tertiary stereogenic centers in yields generally >90%, >20:1 dr, and 97-99% ee.A variety of alkyl-and aryl-substituted allylic esters, α-fluorinated azaaryl acetates, ketones, and amides were amenable to this Cu/Ir catalytic system, giving the desired products with satisfactory results.Notably, the copper catalyst and iridium catalyst could, respectively, control the configuration of the nucleophilic carbon of an unstabilized enolate and the electrophilic carbon of allylic carbonates in this reaction system.
In 2022, Wang and co-workers described a dual Cu/Ir catalytic system for the asymmetric [3+2] annulation of α-fluoro-α-azaaryl acetates 33 with vinylethylene carbonates 36 via a cascade allylic alkylation/lactonization reaction (Scheme 11) [61].In the presence of Cu(CH 3 CN) 4 PF 6 and C10 as a catalyst, (S,S)-L1 as ligand, Et 3 N as a base, α-fluoro-γbutyrolactones 37 containing vicinal stereogenic centers were obtained with 34-98% yields, 16:1->20:1 dr, and 97-99% ee.It is worth noting that all four possible stereoisomers of these valuable products could be readily accessed individually via simple permutations of two chiral catalysts.The proposed mechanism for this In 2019, You et al. reported iridium-catalyzed asymmetric allylic alkylation/fluorination of acyclic ketones 38 (Scheme 12) [62].α-pyridyl-α-fluoroketones 41 bearing vicinal tertiary and fluorine-containing quaternary stereocenters were obtained in 59-97% yields, 4.1:1->19:1 dr, and 93-98% ee by utilizing Me-THQphos (R,R)-L2 as a chiral ligand in the presence of t BuOLi and 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD) in THF at room temperature.Distinct from the above-mentioned stereodivergent synthesis strategies reported by Hartwig [60] and Wang [61], which generally required the use of two different chiral catalysts (Cu/Ir), only one single chiral iridium catalyst was required in You's work, providing an elegant pathway for the stereodivergent synthesis of molecules bearing multiple consecutive stereocenters.All four possible stereoisomers of the desired products were prepared from the same pyridone derivatives as substrates by simply adjusting the sequence of fluorination and allylic alkylation and changing the absolute configuration of the iridium catalyst.
two different chiral catalysts (Cu/Ir), only one single chiral iridium catalyst was required in You's work, providing an elegant pathway for the stereodivergent synthesis of molecules bearing multiple consecutive stereocenters.All four possible stereoisomers of the desired products were prepared from the same pyridone derivatives as substrates by simply adjusting the sequence of fluorination and allylic alkylation and changing the absolute configuration of the iridium catalyst.Scheme 12. Iridium-catalyzed asymmetric allylic alkylation/fluorination of acyclic ketones [62].
process to form the π-allylpalladium intermediate A. Then, deproto fluorinated α-benzothiazylacetate and π-σ isomerization of the allyl skele the ion pair complex B, wherein 2,5-DPBQ might be adjacent to the eno hydrogen-bonding interaction.Finally, the intermediate B underwent an allylation to yield the desired product and regenerate the Pd-L3 catalyst.Scheme 13.Palladium-catalyzed asymmetric allylic C-H alkylation reaction of all fluorinated α-benzothiazylacetates [63].
We also noted that Wolf et al. reported asymmetric fluoroenolate alkyla acetate/carbonate 47 under palladium catalysis using (S)-t-Bu-PHOX (L ligand (Scheme 14) [64].Versatile 3, 3-disubstituted fluorooxindoles 48 b chirality centers were synthesized in 86-98% yields, 88:12->99:1 dr, and addition, the regioselective asymmetric alkylation of nonsymmetrically sub acetates was studied, and the corresponding products were obtained w regioselectivities.The stereochemical outcome of this reaction can be rati preferential attack occurring from the Si face of the fluoroenolate at the a that is trans to the P atom of the L4 in a favored exo-η 3 -allyl Pd complex.We also noted that Wolf et al. reported asymmetric fluoroenolate alkylation with allyl acetate/carbonate 47 under palladium catalysis using (S)-t-Bu-PHOX (L4) as a chiral ligand (Scheme 14) [64].Versatile 3, 3-disubstituted fluorooxindoles 48 bearing vicinal chirality centers were synthesized in 86-98% yields, 88:12->99:1 dr, and ≥99% ee.In addition, the regioselective asymmetric alkylation of nonsymmetrically substituted allylic acetates was studied, and the corresponding products were obtained with excellent regioselectivities.The stereochemical outcome of this reaction can be rationalized by a preferential attack occurring from the Si face of the fluoroenolate at the allylic position that is trans to the P atom of the L4 in a favored exo-η 3 -allyl Pd complex.This pathway provides the (R,R,E) isomer 48f as the major product, whereas an attack originating from the Re face of the fluoroenolate results in the formation of the minor (S,R,E) diastereomer 48e (Scheme 14).
Molecules 2024, 29, x FOR PEER REVIEW 15 of 48 the Re face of the fluoroenolate results in the formation of the minor (S,R,E) diastereomer 48e (Scheme 14).The preparation of arylfluoroacetonitrile derivatives bearing two or more vicinal stereogenic centers via enantioselective C-C bond formation using arylfluoroacetonitrile as a starting material is challenging due to the relatively low C-H acidity of arylfluoroacetonitriles, the possibility of decomposition or HF elimination the side reaction of fluoroacetonitrile under basic conditions, and the difficulty in controlling the stereoselectivity of α-fluoronitrile carbanions [65][66][67][68][69].To tackle the aforementioned challenges, Wolf and co-workers developed a palladium-catalyzed asymmetric allylic alkylation with α-aryl-α-fluoroacetonitriles 49 in the presence of phosphinoxazoline ligand L4 and DBU at −20 °C in acetonitrile (Scheme 15) [70].This reaction afforded the target product 50 featuring two contiguous chirality centers in 60-78% yields, 5:1->15:1 dr, and ≥98% ee.The gram-scale synthesis of this method was also carried out, and good yield and stereochemical outcomes (>99% ee) were obtained.Additionally, asymmetric allylic alkylation products can be further derivatized via Stille cross-coupling reaction without obvious HF elimination.Scheme 14. Palladium-catalyzed asymmetric fluoroenolate alkylation with allyl acetate/carbonate [64].
The preparation of arylfluoroacetonitrile derivatives bearing two or more vicinal stereogenic centers via enantioselective C-C bond formation using arylfluoroacetonitrile as a starting material is challenging due to the relatively low C-H acidity of arylfluoroacetonitriles, the possibility of decomposition or HF elimination the side reaction of fluoroacetonitrile under basic conditions, and the difficulty in controlling the stereoselectivity of α-fluoronitrile carbanions [65][66][67][68][69].To tackle the aforementioned challenges, Wolf and co-workers developed a palladium-catalyzed asymmetric allylic alkylation with α-aryl-αfluoroacetonitriles 49 in the presence of phosphinoxazoline ligand L4 and DBU at −20 • C in acetonitrile (Scheme 15) [70].This reaction afforded the target product 50 featuring two contiguous chirality centers in 60-78% yields, 5:1->15:1 dr, and ≥98% ee.The gram-scale synthesis of this method was also carried out, and good yield and stereochemical outcomes (>99% ee) were obtained.Additionally, asymmetric allylic alkylation products can be further derivatized via Stille cross-coupling reaction without obvious HF elimination.
Recently, the same group employed a similar strategy to realize an asymmetric hydromonofluoroalkylation reaction of 1,3-diene 53 (Scheme 17a) [87].A series of alkyl fluorine derivatives 54, bearing a quaternary F-stereogenic center and vicinal tertiary stereogenic carbon center, were synthesized in yields up to 99%, >20:1 dr, and >99% ee.Intriguingly, all four stereoisomers of corresponding products can also be stereodivergently synthesized through Cu/Pd co-catalysis by using L1, L5, or L6 as chiral ligands.The Pd/L7 or Pd/L8-catalyzed asymmetric hydromonofluoroalkylation reaction of monosubstituted and internal dienes 56 was also developed to access alkyl fluorides in up to 99% yield, >20:1 rr, and 95% ee (Scheme 17b).In addition, asymmetric migratory monofluoroalkylation of skipping dienes 58 was established to realize the straightforward allylic C-H fluoroalkylation (Scheme 17c).Pleasantly, a variety of enantioenriched fluorinated rings can be obtained by diverse transformations.Copper-and palladium-catalyzed asymmetric hydrofunctionalization of conjugated enyenes [86].
of monosubstituted and internal dienes 56 was also developed to access alkyl fluorid up to 99% yield, >20:1 rr, and 95% ee (Scheme 17b).In addition, asymmetric migra monofluoroalkylation of skipping dienes 58 was established to realize the straightforw allylic C-H fluoroalkylation (Scheme 17c).Pleasantly, a variety of enantioenric fluorinated rings can be obtained by diverse transformations.

Mannich Addition Reactions
The catalytic asymmetric Mannich reaction of fluorinated nucleophiles provides an efficient route for the synthesis of pharmaceutically important fluorinated amino compounds [88,89].The efficient organocatalytic asymmetric Mannich reaction of α-fluorinated β-ketoesters, α-fluorinated β-keto acyloxazolidinone, and α-fluorinated aromatic ketones for the synthesis of corresponding products featuring fluorinated tetrasubstituted carbon centers have been reported by Huang, Lu [90] and Jiang, Tan et al. [91,92].In 2016, Wennemers and co-workers reported asymmetric addition reactions of α-fluorinated monothiomalonates 60 to protected imines 61, providing various acyclic α-fluorinated β-amino thioesters 62 in 80-99% yields, 4:1->20:1 dr, and 91-99.9%ee (Scheme 18) [93].The reaction was carried out under mild conditions, and only 1 mol% of epi-quininederived squaramide catalyst (C11) was used.Later, Yan, Song et al. reported an asymmetric organocatalytic Mannich reaction for the synthesis of β-fluoroamine derivatives 65 bearing quaternary C-F centers (Scheme 19) [94].In the presence of Song's chiral oligoEG (C12) as a cation binding catalyst and KF as a base, α-fluoro cyclic ketones 63 were used as nucleophiles to react with α-aminosulfones 64 (as the imine surrogates) to give corresponding products in high yields (36-99%) with good enantioselectivities (88-99% ee) and diastereoselectivities (1:2-1:20 syn:anti).The proposed reaction mechanism is shown in Scheme 19.Firstly, KF was complexed with catalyst C12 to form Int I, which then complexed with amidinosulfone 64 to generate the Int II.Subsequently, the sulfite group on the 64 was removed to obtain the imine-activated Int III.The subsequent coordination of potassium enolate (generated in situ from 63 with KF) to the catalyst was followed by its addition to the imine to provide the products 65.It is noteworthy that the binding of the cation (K + ) to the catalyst was instrumental in instigating both high reactivity and excellent enantioselectivity during the enantio-determining step by the formation of the chiral cage.Later, a similar catalytic system was applied to the asymmetric Mannich reaction of 3-fluoro-oxindoles 66 with α-amidosulfones 64 by the same research group (Scheme 20) [95].α-amidosulfones bearing different aryl and heteroaryl substituents were compatible with generating chiral α-fluoro-β-amino-oxindole derivatives 67 possessing two contiguous stereogenic centers in 63-97% yields, 1:1->20:1 dr, and 81-99% ee (syn).Unfortunately, alkyl α-amidosulfone was unsuitable for this reaction.

Mannich Addition Reactions
The catalytic asymmetric Mannich reaction of fluorinated nucleophiles provides an efficient route for the synthesis of pharmaceutically important fluorinated amino compounds [88,89].The efficient organocatalytic asymmetric Mannich reaction of αfluorinated β-ketoesters, α-fluorinated β-keto acyloxazolidinone, and α-fluorinated aromatic ketones for the synthesis of corresponding products featuring fluorinated tetrasubstituted carbon centers have been reported by Huang, Lu [90] and Jiang, Tan et al. [91,92].In 2016, Wennemers and co-workers reported asymmetric addition reactions of αfluorinated monothiomalonates 60 to protected imines 61, providing various acyclic αfluorinated β-amino thioesters 62 in 80-99% yields, 4:1->20:1 dr, and 91-99.9%ee (Scheme 18) [93].The reaction was carried out under mild conditions, and only 1 mol% of epiquininederived squaramide catalyst (C11) was used.Later, Yan, Song et al. reported an asymmetric organocatalytic Mannich reaction for the synthesis of β-fluoroamine derivatives 65 bearing quaternary C-F centers (Scheme 19) [94].In the presence of Song's chiral oligoEG (C12) as a cation binding catalyst and KF as a base, α-fluoro cyclic ketones 63 were used as nucleophiles to react with α-aminosulfones 64 (as the imine surrogates) to give corresponding products in high yields (36-99%) with good enantioselectivities (88-99% ee) and diastereoselectivities (1:2-1:20 syn:anti).The proposed reaction mechanism is shown in Scheme 19.Firstly, KF was complexed with catalyst C12 to form Int I, which then complexed with amidinosulfone 64 to generate the Int II.Subsequently, the sulfite group on the 64 was removed to obtain the imine-activated Int III.The subsequent coordination of potassium enolate (generated in situ from 63 with KF) to the catalyst was followed by its addition to the imine to provide the products 65.It is noteworthy that the binding of the cation (K + ) to the catalyst was instrumental in instigating both high reactivity and excellent enantioselectivity during the enantiodetermining step by the formation of the chiral cage.Later, a similar catalytic system was applied to the asymmetric Mannich reaction of 3-fluoro-oxindoles 66 with αamidosulfones 64 by the same research group (Scheme 20) [95].α-amidosulfones bearing different aryl and heteroaryl substituents were compatible with generating chiral αfluoro-β-amino-oxindole derivatives 67 possessing two contiguous stereogenic centers in 63-97% yields, 1:1->20:1 dr, and 81-99% ee (syn).Unfortunately, alkyl α-amidosulfone was unsuitable for this reaction.Scheme 18. Asymmetric organocatalyzed addition reactions of α-fluorinated monothiomalonates to protected imines [93].
Subsequently, Wolf and co-workers used a similar strategy to realize a Cu-catalyzed asymmetric Mannich reaction of α-fluorinated arylacetonitrile 49 with isatin-derived N-Boc ketimines 83 (Scheme 26) [102].Anti-diastereomers of multifunctionalized 3-aminooxindoles 84 bearing two adjacent tetrasubstituted stereocenters were obtained in 81-99% yields, 8.5:1->50:1 dr, and 84-97% ee when L6 was used as a chiral ligand and the N-protecting group of isatin was triphenylmethyl.When L12 was used as a chiral ligand and the Nprotecting group of isatin was phenyl, syn-diastereomers of 3-aminooxindoles 85 possessing a quaternary carbon-fluorine stereocenter were synthesized in 84-99% yields, 3:1-7:1 dr, and 83-97% ee.The Mannich products can be converted to other useful molecules via selective transformations of oxindole ring opening and nitrile functionality.Additionally, a gram scale experiment was also carried out to probe the utility of this reaction, and the desired anti-α-fluoro-β-aminonitrile was prepared in excellent yield (0.94 g, 99% yield) with 12.7:1 dr and 90% major ee.They proposed a plausible catalytic cycle, shown in Scheme 26.Firstly, α-fluorinated arylacetonitrile was coordinated to the (L6) Cu(I) complex to form complex A, which then underwent reversible deprotonation in the presence of BTMG to form the cuprous keteniminate complex B. Subsequently, the isatin ketimine was attacked from the Si face of complex B to form complex C through irreversible C-C bond formation.Finally, complex C underwent proton transfer and dissociation to yield the desired product and regenerate the free CuI complex and BTMG.ketimine was attacked from the Si face of complex B to form complex C through irreversible C-C bond formation.Finally, complex C underwent proton transfer and dissociation to yield the desired product and regenerate the free CuI complex and BTMG

Michael Addition Reactions
The asymmetric Michael addition reaction is the other effective method used to construct continuous stereocenters containing fluorine atoms.In 2014, Lu and co-worker reported that quinine-derived sulfonamide C13 catalyzed asymmetric Michael addition reactions with nitroalkenes 87 as acceptors to react with 2-fluoro-1,3 diketones 86 (Schem 27) [103].Several aryl methyl diketones reacted very well with aryl nitroolefins, and th corresponding Michael adducts 88 were obtained in good chemical yields (70-95%) excellent enantioselectivities (89->99% ee), but moderate diastereoselectivties (2:1-8:1 dr) However, the isopropyl-substituted nitroalkenes substrate showed moderate reactivity and low stereoselectivity with almost no stereoselectivity.The proposed transition-stat model is shown in Scheme 27.They believe that the hydrogen-bonding interaction between the nitro group of nitroalkenes and the NH group of sulfonamides is crucial fo the observed stereoselectivity.In the same year, an enantioselective Michael addition o α-fluoro-α-nitroalkanes 89 to nitroolefins 87 was developed by the same group (Schem 28) [104].They used amino acid-incorporating multifunctional quinine-derived compound C14 as the organocatalyst for this reaction, which provided the desired Scheme 26.Symmetric Mannich reactions of α-fluoro-α-arylnitriles with isatin ketimines [102].

Michael Addition Reactions
The asymmetric Michael addition reaction is the other effective method used to construct continuous stereocenters containing fluorine atoms.In 2014, Lu and co-workers reported that quinine-derived sulfonamide C13 catalyzed asymmetric Michael addition reactions with nitroalkenes 87 as acceptors to react with 2-fluoro-1,3 diketones 86 (Scheme 27) [103].Several aryl methyl diketones reacted very well with aryl nitroolefins, and the corresponding Michael adducts 88 were obtained in good chemical yields (70-95%), excellent enantioselectivities (89->99% ee), but moderate diastereoselectivties (2:1-8:1 dr).However, the isopropyl-substituted nitroalkenes substrate showed moderate reactivity and low stereoselectivity with almost no stereoselectivity.The proposed transition-state model is shown in Scheme 27.They believe that the hydrogen-bonding interaction between the nitro group of nitroalkenes and the NH group of sulfonamides is crucial for the observed stereoselectivity.In the same year, an enantioselective Michael addition of α-fluoro-α-nitroalkanes 89 to nitroolefins 87 was developed by the same group (Scheme 28) [104].They used amino acid-incorporating multifunctional quinine-derived compound C14 as the organocatalyst for this reaction, which provided the desired products 90 in 71-95% yields, 5:1-8:1 dr, and 82-96% ee.Different α-aryl-α-fluoronitromethanes, as well as various aromatic and aliphatic nitroolefins, were suitable substrates for this Michael reaction.However, simple alkyl-substituted α-fluoro-α-nitroalkanes were unsuitable substrates.Intriguingly, different diastereomers of the Michael addition products could be isolated by a regular flash silica gel chromatographic column.The proposed stereochemical model is shown in Scheme 28.They believed that bifunctional activation of the substrates was important for the observed stereoselectivity.
Molecules 2024, 29, x FOR PEER REVIEW 27 of 48 products 90 in 71-95% yields, 5:1-8:1 dr, and 82-96% ee.Different α-aryl-αfluoronitromethanes, as well as various aromatic and aliphatic nitroolefins, were suitable substrates for this Michael reaction.However, simple alkyl-substituted α-fluoro-αnitroalkanes were unsuitable substrates.Intriguingly, different diastereomers of the Michael addition products could be isolated by a regular flash silica gel chromatographic column.The proposed stereochemical model is shown in Scheme 28.They believed that bifunctional activation of the substrates was important for the observed stereoselectivity.products 90 in 71-95% yields, 5:1-8:1 dr, and 82-96% ee.Different α-aryl-αfluoronitromethanes, as well as various aromatic and aliphatic nitroolefins, were suitable substrates for this Michael reaction.However, simple alkyl-substituted α-fluoro-αnitroalkanes were unsuitable substrates.Intriguingly, different diastereomers of the Michael addition products could be isolated by a regular flash silica gel chromatographic column.The proposed stereochemical model is shown in Scheme 28.They believed that bifunctional activation of the substrates was important for the observed stereoselectivity.In 2015, Zhou et al. developed asymmetric Michael addition of monofluorinated enol silyl ethers 91 to isatylidene malononitriles 92 (Scheme 29) [105].They used chiral secondary amine phosphoramide C15 as the organocatalyst for this reaction, which afforded the corresponding monofluorinated oxindole derivatives 93 bearing adjacent and tetrasubstituted carbon stereocenters in excellent chemical yields (95-99%) and high enantioselectivities (84-94% ee) and diastereoselectivities (4:1->20:1 dr).The product could be transformed into the polycyclic compound in the presence of NaBH 4 without loss of enantioselectivity.
Recently, Singh et al. reported a Cu-catalyzed enantioselective Michael addition reaction between alkyl azaarenes 33 and α,β-unsaturated 2-acyl imidazoles 98 (Scheme 32) [108].A range of 2-alkyl azaarene derivatives bearing vicinal quaternary-tertiary stereocenters were synthesized with a high level of chemical yields (up to 97%), diastereoselectivities (>20:1), and enantioselectivities (up to 99%) in the presence of 5.5 mol% (S,S)-L1 and 5 mol% DBU.The substrates scope was investigated, and α,β-unsaturated 2-acyl imidazoles with different ortho-, meta-, and para-substitution patterns and heteroaromatic rings substrates were well tolerated, affording excellent yields and enantioselectivities. Surprisingly, under optimized reaction conditions, the yields and selectivity decreased significantly when R 2 = Me, OMe, Ph.In addition, benzothiazolyl fluoroacetate substrates with electrondonating, electron-withdrawing, halogenated, and heteroaryl substituents proceeded well.1,6-Michael receptor substrates also reacted smoothly, with the addition reaction occurring only at the 1,4-position.The proposed transition-state model, illustrated in Scheme 32, postulated that the high stereoselectivity was primarily attributed to the binding of chiral Cu(I)-bisphosphines to both the nitrogen of the azaarene ring and the ester carbonyl oxygen of 33.This binding configuration effectively obstructed one face of the azaarene 33 with the ligand substituent, thereby directing the reaction toward high stereoselectivity.
Molecules 2024, 29, x FOR PEER REVIEW 30 of 48 unsaturated 2-acyl imidazoles with different ortho-, meta-, and para-substitution patterns and heteroaromatic rings substrates were well tolerated, affording excellent yields and enantioselectivities. Surprisingly, under optimized reaction conditions, the yields and selectivity decreased significantly when R 2 = Me, OMe, Ph.In addition, benzothiazolyl fluoroacetate substrates with electron-donating, electron-withdrawing, halogenated, and heteroaryl substituents proceeded well.1,6-Michael receptor substrates also reacted smoothly, with the addition reaction occurring only at the 1,4-position.The proposed transition-state model, illustrated in Scheme 32, postulated that the high stereoselectivity was primarily attributed to the binding of chiral Cu(I)-bisphosphines to both the nitrogen of the azaarene ring and the ester carbonyl oxygen of 33.This binding configuration effectively obstructed one face of the azaarene 33 with the ligand substituent, thereby directing the reaction toward high stereoselectivity.
In 2023, Lee et al. reported a stereodivergent conjugate addition reaction for the preparation of tertiary alkyl fluorides in adjacent stereogenic pairs (Scheme 33) [109].They used α-fluoro azaaryl acetamides as the α-fluoroenolate precursor to react with in situgenerated chiral iminium electrophiles from α,β-unsaturated aldehydes 100.The products, 4-fluorinated 1,5-aldehyde amides 101, were obtained in generally good yields with high stereocontrol.Most of the adducts were isolated after the reduction of aldehyde to alcohol 102, during which the diastereomeric ratio did not change.All four stereoisomers of the desired products with vicinal stereocenters were synthesized by variation of the combinations of the enantiomers of phosphine ligand L1 and amine C18.It is worth mentioning that this stereodivergent conjugate addition strategy, combined with aminocatalytic asymmetric α-fluorination, enabled the rapid synthesis of all eight stereoisomers of molecules bearing three contiguous stereocenters containing two fluorinated stereocenters.
Molecules 2024, 29, x FOR PEER REVIEW 31 of 48 In 2023, Lee et al. reported a stereodivergent conjugate addition reaction for the preparation of tertiary alkyl fluorides in adjacent stereogenic pairs (Scheme 33) [109].They used α-fluoro azaaryl acetamides as the α-fluoroenolate precursor to react with in situgenerated chiral iminium electrophiles from α,β-unsaturated aldehydes 100.The products, 4-fluorinated 1,5-aldehyde amides 101, were obtained in generally good yields with high stereocontrol.Most of the adducts were isolated after the reduction of aldehyde to alcohol 102, during which the diastereomeric ratio did not change.All four stereoisomers of the desired products with vicinal stereocenters were synthesized by variation of the combinations of the enantiomers of phosphine ligand L1 and amine C18.It is worth mentioning that this stereodivergent conjugate addition strategy, combined with aminocatalytic asymmetric α-fluorination, enabled the rapid synthesis of all eight stereoisomers of molecules bearing three contiguous stereocenters containing two fluorinated stereocenters.

Aldol Addition Reactions
In 2014, Zhou et al. reported an organocatalytic asymmetric aldol addition reaction for the synthesis of optically active 3-hydroxyoxindole derivatives 104 with two adjacent tetrasubstituted carbon stereocenters featuring a C-F bond (Scheme 34) [110].They used prochiral monofluorinated enol ethers 91 to react with isatins 103 in the presence of cinchona alkaloid-derived bifunctional (thio)urea catalysts C19 or urea-tertiary amine catalyst C20.The solvent had a significant effect on the reaction results, and MeCN was Scheme 33.Asymmetric conjugate addition reaction between α,β-unsaturated aldehydes and α-fluoro azaaryl acetamides [109].

Aldol Addition Reactions
In 2014, Zhou et al. reported an organocatalytic asymmetric aldol addition reaction for the synthesis of optically active 3-hydroxyoxindole derivatives 104 with two adjacent tetrasubstituted carbon stereocenters featuring a C-F bond (Scheme 34) [110].They used prochiral monofluorinated enol ethers 91 to react with isatins 103 in the presence of cinchona alkaloid-derived bifunctional (thio)urea catalysts C19 or urea-tertiary amine catalyst C20.The solvent had a significant effect on the reaction results, and MeCN was considered the best reaction medium.In the cases of isatins without electron-withdrawing substituents, the reactions were carried out using organocatalyst C19, providing the desired products 104 in high chemical yields (37-98% yield), excellent enantioselectivities (70-94% ee), and good diastereoselectivities (5:1-15:1 dr).However, when 5-halo groups substituted isatins were used as substrates, the corresponding products were obtained in 5:1 dr and 81-86% ee in the presence of urea-tertiary amine catalyst C20.It should be noted that acyclic monofluorinated silyl enol ether was able to react with isatin under the same conditions, affording the expected product with a moderate yield (46%) and stereochemical outcome (2:1 dr, 81% ee).
In 2016, Wennemers and Saadi used fluoromalonic acid halfthioesters (F-MA 113) as fluoroacetate surrogates for the asymmetric aldol addition reaction (Scheme [120].The quinidine-urea catalyst C21 was chosen as the best organocatalyst for this a reaction, which could catalyze this reaction smoothly to give the correspon fluorinated thioesters 114 with up to 87% yields, 17:1 dr, and 99% ee.Both the m reactive aromatic aldehydes and the less-reactive aliphatic aldehydes were well toler to react with electron-rich 4-methoxythiophenol-derived F-MAHT or 2-fluorothiophe derived F-MAHT.They also utilized the pseudo-enantiomer quinine-derived catalyst for this reaction and provided the mirror image product with high yields stereoselectivities, similar to the corresponding enantiomers.Gladly, the anti-and diastereoisomers could be easily separated by column chromatography, and the m syn-isomers were obtained in high enantioselectivities equal to the corresponding m anti-isomers.Scheme 38.Cu-catalyzed asymmetric aldol reaction between 3-fluoro-2-oxindole derived enolate precursors and aldehydes [119]. In 2016, Wennemers and Saadi used fluoromalonic acid halfthioesters (F-MAHTs, 113) as fluoroacetate surrogates for the asymmetric aldol addition reaction (Scheme 39) [120].The quinidine-urea catalyst C21 was chosen as the best organocatalyst for this aldol reaction, which could catalyze this reaction smoothly to give the corresponding fluorinated thioesters 114 with up to 87% yields, 17:1 dr, and 99% ee.Both the more-reactive aromatic aldehydes and the less-reactive aliphatic aldehydes were well tolerated to react with electron-rich 4-methoxythiophenol-derived F-MAHT or 2-fluorothiophenol-derived F-MAHT.They also utilized the pseudo-enantiomer quinine-derived catalyst C22 for this reaction and provided the mirror image product with high yields and stereoselectivities, similar to the corresponding enantiomers.Gladly, the antiand syn-diastereoisomers could be easily separated by column chromatography, and the minor syn-isomers were obtained in high enantioselectivities equal to the corresponding major anti-isomers.
In 2020, Kumagai, Shibasaki et al. developed a Cu-catalyzed asymmetric aldol addition reaction between α-fluoronitriles 49 and aldehydes 105/107 (Scheme 40) [121].The reaction used L6 as the chiral ligand and conducted the reaction at −80 • C in the presence of asymmetrical achiral thioureas TU2 as a secondary ligand and Barton's base.Nitriles with electron-donating and electron-withdrawing substituents and aliphatic and aromatic aldehydes were well tolerated to give the desired α-fluoro-β-hydroxynitriles 115 featuring two vicinal stereogenic centers with 70-89% yields, 1:1-16:1 dr, and 70-99% ee.The stereoselectivity of this chiral CuI/Barton's base catalytic system could be significantly enhanced by the combined use of trimethylthiourea TU2.In 2020, Kumagai, Shibasaki et al. developed a Cu-catalyzed asymmetric aldol addition reaction between α-fluoronitriles 49 and aldehydes 105/107 (Scheme 40) [121].The reaction used L6 as the chiral ligand and conducted the reaction at −80 °C in the presence of asymmetrical achiral thioureas TU2 as a secondary ligand and Barton's base.Nitriles with electron-donating and electron-withdrawing substituents and aliphatic and aromatic aldehydes were well tolerated to give the desired α-fluoro-β-hydroxynitriles 115 featuring two vicinal stereogenic centers with 70-89% yields, 1:1-16:1 dr, and 70-99% ee.The stereoselectivity of this chiral CuI/Barton's base catalytic system could be significantly enhanced by the combined use of trimethylthiourea TU2.
In 2022, Córdova and Himo et al. reported a solvent dependency in the stereoselective intramolecular amidation reaction of chiral 5-inofunctionalized-2-fluoromalonate ester derivatives in the presence of a chiral catalyst C24 (Scheme 43) [124].In solvents with dielectric constants (ε) less than 10 (e.g., CH2Cl2), δ-lactams 123/125 with a synconfiguration between adjacent tertiary carbon and fluorine-containing quaternary stereocenters were generally generated.In solvents with ε > 15 (e.g., MeOH), the corresponding δ-lactams 124/126 with anti-configuration were formed.This catalytic asymmetric cascade reaction combined with solvent-directed stereoselective reactions provided a novel strategy for the stereodivergent synthesis of all possible stereoisomers of heterocyclic compounds with two vicinal stereogenic centers featuring C-F quaternary stereocenters.
In 2022, Córdova and Himo et al. reported a solvent dependency in the stereoselective intramolecular amidation reaction of chiral 5-inofunctionalized-2-fluoromalonate ester derivatives in the presence of a chiral catalyst C24 (Scheme 43) [124].In solvents with dielectric constants (ε) less than 10 (e.g., CH 2 Cl 2 ), δ-lactams 123/125 with a syn-configuration between adjacent tertiary carbon and fluorine-containing quaternary stereocenters were generally generated.In solvents with ε > 15 (e.g., MeOH), the corresponding δ-lactams 124/126 with anti-configuration were formed.This catalytic asymmetric cascade reaction combined with solvent-directed stereoselective reactions provided a novel strategy for the stereodivergent synthesis of all possible stereoisomers of heterocyclic compounds with two vicinal stereogenic centers featuring C-F quaternary stereocenters.
stereocenters were generally generated.In solvents with ε > 15 (e.g., MeOH), the corresponding δ-lactams 124/126 with anti-configuration were formed.This catalyti asymmetric cascade reaction combined with solvent-directed stereoselective reaction provided a novel strategy for the stereodivergent synthesis of all possible stereoisomer of heterocyclic compounds with two vicinal stereogenic centers featuring C-F quaternary stereocenters.
In 2022, Hoveyda, Liu et al. developed an in situ-generated Zn(O t Bu)Et/aminophenol (L16) complex catalyzed highly regio-, diastereo-, and enantioselective reactions between fluoro-substituted allylboronates 128 and aldehydes (Scheme 44) [125].Diverse aryl-, heteroaryl-, alkenyl-, and alkyl-substituted aldehydes were well tolerated in this catalytic system to give homoallylic alcohols 129 with adjacent stereogenic carbon centers containing a trifluoromethyl-and a fluoro-substituted stereogenic center.It is worth noting that the electrophilicity of aldehydes affected γ selectivity, and the more electron-rich aldehydes provided higher γ selectivity.In contrast, γ:α selectivity was lower for the more electrondeficient aldehydes.In 2022, Hoveyda, Liu et al. developed an in situ-generated Zn(O t Bu)Et/aminophenol (L16) complex catalyzed highly regio-, diastereo-, and enantioselective reactions between fluoro-substituted allylboronates 128 and aldehydes (Scheme 44) [125].Diverse aryl-, heteroaryl-, alkenyl-, and alkyl-substituted aldehydes were well tolerated in this catalytic system to give homoallylic alcohols 129 with adjacent stereogenic carbon centers containing a trifluoromethyl-and a fluoro-substituted stereogenic center.It is worth noting that the electrophilicity of aldehydes affected γ selectivity, and the more electronrich aldehydes provided higher γ selectivity.In contrast, γ:α selectivity was lower for the more electron-deficient aldehydes.
We also noted that Hartwig et al. reported an iridium-catalyzed enantioselective allylic substitution reaction between 3-fluoro allylic electrophiles and soft carbon nucleophiles.Encouragingly, diastereoselective fluoroalkylation of ethyl 2-oxocyclohexanecarboxylate 137 with 3-fluoroallyl phosphate 136 in the presence of the ent-C26 catalyst processed smoothly to give desired diastereomers with two consecutive stereogenic centers in suitable yields with moderate diastereo-and enantioselectivity (Scheme 46) [127].In 2020, Hartwig et al. developed the iridium-catalyzed desymmetrization of allylic difluoromethylene groups to afford optically pure tertiary allylic fluorides 143 with high yield, regioselectivity, and enantioselectivity via the activation of a single C-F bond.The participation of a prochiral β-keto ester in the reaction gave allyl fluorides with two contiguous, fully substituted stereocenters containing one fluorine atom with good diastereoselectivity (6:1 dr) and excellent enantioselectivity (96% ee) (Scheme 47) [128].
Molecules 2024, 29, x FOR PEER REVIEW allylic fluorides 143 with high yield, regioselectivity, and enantioselectiv activation of a single C-F bond.The participation of a prochiral β-keto ester in t gave allyl fluorides with two contiguous, fully substituted stereocenters con fluorine atom with good diastereoselectivity (6:1 dr) and excellent enantioselec ee) (Scheme 47) [128].

Conclusions
Fluorinated compounds are important molecules that are widely used in materia sciences, pharmaceuticals, agrochemicals, and other fields.Particularly, fluorine containing compounds with complex and variable structures and multiple continuous stereocenters have attracted much attention.This review summarizes the importan research progress in the synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers in recent years, including the asymmetric electrophilic fluorination and asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions Michael addition reactions, Aldol addition reactions, and miscellaneous reactions), and with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms.The success of these methods is attributed to the ingenious design o catalysts/substrates/reaction modes.We hope that this review will provide new ideas fo the discovery of more common and efficient new catalysts/methods/reagents for the synthesis of high-value fluorinated compounds and their derivatives.

Conclusions
Fluorinated compounds are important molecules that are widely used in material sciences, pharmaceuticals, agrochemicals, and other fields.Particularly, fluorine-containing compounds with complex and variable structures and multiple continuous stereocenters have attracted much attention.This review summarizes the important research progress in the synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers in recent years, including the asymmetric electrophilic fluorination and asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, Aldol addition reactions, and miscellaneous reactions), and with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms.The success of these methods is attributed to the ingenious design of catalysts/substrates/reaction modes.We hope that this review will provide new ideas for the discovery of more common and efficient new catalysts/methods/reagents for the synthesis of high-value fluorinated compounds and their derivatives.

Figure 2 .
Figure 2. Chiral ligands for the asymmetric synthesis of alkyl fluorides bearing multiple con stereogenic centers.

Figure 2 .
Figure 2. Chiral ligands for the asymmetric synthesis of alkyl fluorides bearing multiple contiguous stereogenic centers.

Figure 3 .
Figure 3. Chiral catalysts and metals complexes for the asymmetric synthesis of alkyl fluorides bearing multiple contiguous stereogenic centers.

Figure 3 .
Figure 3. Chiral catalysts and metals complexes for the asymmetric synthesis of alkyl fluorides bearing multiple contiguous stereogenic centers.
Asymmetric electrophilic fluorination catalyzed by transition metal catalysts or chiral organocatalysts is one of the typical methods used for the synthesis of chiral alkyl fluorinated compounds with multiple contiguous stereogenic centers containing a C-F quaternary carbon.The diastereo-and enantioselective electrophilic fluorination mainly includes asymmetric fluorinative dearomatization, sequential asymmetric addition/fluorination, and asymmetric cyclization/fluorination.Molecules 2024, 29, x FOR PEER REVIEW 5 chiral alkyl fluorinated compounds with multiple contiguous stereogenic ce containing a C-F quaternary carbon.The diastereo-and enantioselective electro fluorination mainly includes asymmetric fluorinative dearomatization, sequ asymmetric addition/fluorination, and asymmetric cyclization/fluorination.

Figure 4 .
Figure 4.The common electrophilic and nucleophilic fluorinating reagents used for ca asymmetric fluorination.

Figure 4 .
Figure 4.The common electrophilic and nucleophilic fluorinating reagents used for catalytic asymmetric fluorination.Catalytic asymmetric dearomatization (CADA) [32-39] reactions via fluorination represent a powerful strategy for constructing chiral fluorine-containing compounds from readily available aromatic derivatives.In 2011, Gouverneur et al. reported the first organocatalyzed asymmetric dearomatization of indole derivatives 13 via cascade fluorocyclization utilizing a cinchona alkaloid C1 as a catalyst and NFSI or Selectfluor as an electrophilic reagent (Scheme 1) [40].Enantioenriched fluorinated heterocycles 14 were obtained with moderate to high enantioselectivities.Almost at the same time, Toste et al. developed asymmetric electrophilic fluorination using a chiral anion phase-transfer catalyst C2.Interestingly, benzothiophenes substrates 15 were converted to desired fluorocyclization products 16 in high optical purity and good yield through CADA reactions via fluorination (Scheme 2) [25].The proposed catalytic mechanism is shown in Scheme 2. Phosphate (2 equiv.)undergoes salt substitution with Selectfluor to produce the chiral ion pair, which is soluble in nonpolar solvents, and then the chiral ion pair can mediate the fluorocyclization of the substrate 17.In 2017, You et al. developed asymmetric fluorinative dearomatization of tryptamine derivatives 19 under anion phase-transfer catalysis, which entailed the use of Selectfluor as an electrophilic fluoride source and a chiral phosphate anion derived from BINOL backbone C3 as a catalyst (Scheme 3)[41].They noticed that a proton sponge (PS) can effectively improve the reaction yield.A variety of fluorinated pyrroloindolines 20 bearing two contiguous quaternary stereogenic centers were obtained with excellent enantioselectivities (up to 97% ee) and high yields (up to 92% yield).Regarding the exploration of the substrates' scope, tryptamines with electron-withdrawing protecting groups (Boc, CO 2 Me, Cbz, and Fmoc) were well tolerated.N-Boc protected tryptamines with different electron-withdrawing (5-CO 2 Et, 5-CF 3 , 5-Cl, 5-Br, and 5-F) and electron-donating (5-MeO, 5-CH 3 , and 5-t Bu) substituents at the C5 position, which proceeded with excellent enantioselectivity.4,6-dihalo-substituted substrates and 2-or 6-substituent of the indole moiety were also well tolerated to provide target products with high enantioselectivity.Substrates bearing higher steric hindrance substituents or simple H and methyl at the C7 position resulted in moderate enantioselectivity.Control experiments suggested that the reaction proceeded via bifunctional activation using a chiral BINOL-derived phosphate anion C3.Recently, the asymmetric dearomatizing fluoroamidation of indole acetamide derivatives 21 using a dicarboxylate phase-transfer catalyst C4 under mild conditions was developed by Hamashima et al. (Scheme 4)[42].Indoles with various substitution patterns were suitable substrates, providing easy access to chiral fluoropyrroloindoline derivatives 22 in 50-90% yields and 74-97% ee.It is worth mentioning that the addition of an appropriate amount of water to the reaction system was essential to facilitate the reaction and ensure reproducibility.
[3+2] annulation reaction is shown in Scheme 11.Under basic conditions, chiral Cu(I)-(S,S)-L1 could coordinates with the nitrogen atom of the azaarene ring and carbonyl oxygen in α-fluoro-α-azaryl acetate to generate the chiral metalated intermediate A. Simultaneously, the coordination of [(S,S,S)-Ir(I)] C10 with racemic vinylethylene carbonate(±) generated the corresponding complexes [Ir(I) * ]•(R)-B and [Ir(I) * ]•(S)-B.(R)-vinylethylene carbonate (R)-36 could be recovered from the less reactive former species through kinetic resolution, while the latter more reactive species was prioritized to undergo decarboxylative oxidation addition and generate the zwitterionic Ir(III)-π-allyl species C with the configuration inversion.The chiral metalated intermediate A then nucleophilically attacked the Ir(III)-π-allyl species C in a highly Re-Re stereoselective manner to form the allylic alkylation intermediate (2S,3S)-D-Int and regenerate the chiral Cu/Ir catalysts.Finally, the intermediate (2S,3S)-D-Int underwent intramolecular esterification to access target products.
2024, 29, x FOR PEER REVIEW Then, 2-fluoro-1-(2-hydroxyaryl)-1,3-dione 116 attacked the Si face of chiral iminium A and underwent a Michael addition reaction to generate the intermediate B. After the hydrolysis of intermediate B, the catalyst C23 was recovered.Subsequently, the intermediate B underwent cyclic ketonization/hemiacetalization and acylation reactions to give the target products 117.